Synovial inflammatory macrophage-derived extracellular vesicles exacerbate cartilage lesions with a FMRP-selectively sorted manner in osteoarthritis

Abstract

Osteoarthritis (OA) is an aging-related degenerative joint disease without effective therapies. In the early stage of OA, mild synovitis has been reported to induce cartilage lesions. A better understanding of crosstalk between synovial macrophages and chondrocytes are being developed to discover new OA therapeutics. Here, we identified that the extracellular vesicles (EVs) derived from synovial pro-inflammatory macrophages regulated the autophagy function of chondrocytes, induced the onset of cartilage degeneration in normal joints. Mechanistically, the active transfer of miR-155-5p via EVs from synovial pro-inflammatory macrophages to chondrocytes accelerates cartilage degeneration by suppressing GSK-3β/mTORC1 axis-mediated autophagy function during OA progression. Deleting miR-155 from synovial pro-inflammatory macrophages relieved cartilage lesions and synovitis in OA mice. On the other hand, Fragile X mental retardation protein (FMRP) selectively sorted miR-155-5p into EVs derived from synovial pro-inflammatory macrophages, and the levels of plasma EVs FMRP were closely related to OA progression, suggesting the potential candidate for diagnostic OA biomarkers. Based on these findings, we developed engineering EVs with MAP (pro-inflammatory macrophages-affinity peptide) derived from adipose-derived stromal cells (ADSCs) as the antagomiR-155-5p delivery vehicles which exhibited superior therapeutic effects on synovitis and injured cartilage in the surgery-induced OA rats. Furthermore, MAP-ADSCs-EVs were proved to target the polarization of synovial pro-inflammatory macrophages in the clinical OA samples. Collectively, our study indicates that plasma EVs FMRP and engineered MAP-ADSCs-EVs targeting synovial pro-inflammatory macrophages represent potential novel therapeutic strategy for the progression of OA.

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Funding

National Natural Science Foundation of China (National Science Foundation of China)(32170986)

Natural Science Fundation of Shanghai Municipal Science and Technology Commission (24ZR1457800), the National Key Research and Development Program of China (2024YFA1107305), the research project from the health and family planning commission of Hongkou District (HW-2402-08), the Innovation Program of Shanghai Municipal Education Commission (2023ZKZD31),the Scientific Research Launch Project of Shanghai Fourth People's Hospital (sykyqd08061, SY-XKZT-2024-1007)

the Natural Science Fundation of Shanghai Municipal Science and Technology Commission (24ZR1457800), the research project from the health and family planning commission of Hongkou District (HW-2402-08), the Scientific Research Launch Project of Shanghai Fourth People's Hospital (sykyqd08061, SY-XKZT-2024-1007).

RIGHTS & PERMISSIONS

The Author(s)